I cover cardiology news for CardioExchange, a social media website for cardiologists published by the New England Journal of Medicine. I was the editor of TheHeart.Org from its inception in 1999 until December 2008. Following the purchase of TheHeart.Org by WebMD in 2005, I became the editorial director of WebMD professional news, encompassing TheHeart.Org and Medscape Medical News. Prior to joining TheHeart.Org, I was a freelance medical journalist and wrote for a wide variety of medical and computer publications. In 1994-1995 I was a Knight Science Journalism Fellow at MIT. I have a PhD in English from SUNY Buffalo, and I drove a taxicab in New York City before embarking on a career in medical journalism. You can follow me on Twitter at: @cardiobrief.

Disappointing Results with Boehringer's Pradaxa for Mechanical Valves

Despite being more durable than bioprosthetic valves, mechanical heart valves are often not chosen because of the requirement for lifelong anticoagulant therapy. It has been hoped that the newer generation of oral anticoagulants might eventually replace warfarin, making anticoagulation more tolerable and better accepted, since these agents don’t require continuous monitoring and have much fewer serious interactions with other drugs and food. So far, however, there has been no convincing demonstration that the the newer agents are as safe and effective as warfarin for this indication.

RE-ALIGN was a phase 2 dose-validation study of dabigatran (Pradaxa, Boehringer Ingelheim) in patients with mechanical heart valves. Results of the trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine. Patients in the trial were randomized to dabigatran or warfarin.

After 252 patients had been randomized, the trial was stopped early due to an increase in thromboembolic and bleeding events in the dabigatran group:

Among the 162 patients who received dabigatran there were nine ischemic or unspecified strokes and three MIs, compared with no strokes or MIs among the 84 patients randomized to warfarin.

Major bleeding occurred in seven (4%) patients in the dabigatran group versus two (2%) in the warfarin group. Twenty-seven percent of patients in the dabigatran group had a bleeding episode of any type, compared with 12% in the warfarin group. All the major bleeding episodes took place in the first two weeks after surgery.

The trial investigators reported that one-third of the dabigatran patients either discontinued treatment or required a dose adjustment. They speculated that warfarin may be more effective than dabigatran at suppressing the specific coagulation activity associated with valve surgery.

“The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complicaitons in patients who require anticoagulation after the implantation of a prosthetic heart valve,” they wrote. They also warned that the same fate may befall the factor Xa inhibitors, including Xarelto (rivaroxaban) and Eliquis (apixaban), which, like dabigatran, have been approved as an alternative to warfarin for use in atrial fibrillation.

In an accompanying editorial, Elaine Hylek writes that the results may be explained in part by the high percentage of patients with recent surgery. “The early postoperative period may have been less than optimal for testing a new fixed dose regimen because of the enhanced thrombogenicity inherent in such patients.”

Hylek writes that another possible explanation is the use of target trough levels based on the RE-LY trial in patients with AF. “Translation of dose across indications is challenging, given the different mechanisms of thrombus formation in different vascular beds, differences in flow and shear stress… and patients’ characteristics.”

She strongly discourages the clinical use of the newer anticoagulants for this indication at the present time, but holds out hope for their eventual success: ”Off-label use will place patients at undue risk and is rightfully prohibited. The results of RE-ALIGN are disappointing, but there is a palpable downside as well to potential premature abandonment of research into the use of such drugs in patients with mechanical heart valves.”

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If Prof. Van de Werf is right in his assessment of the situation, then only one oral anticoagulant drug candidate (tecarfarin) could become an alternative to warfarin for prosthetic heart valve patients. Tecarfarin was recently investigated in a late stage clinical trial (EMBRACE-AC) where 14% of the patients in the study (% also ~ “real world” prevalence) had mechanical heart valves.

From ESC Congress 2013. “Dabigatran etexilate has been shown to be effective and safe in other indications, and there are several potential reasons for these results ” said Prof. Van de Werf. “The presence of a mechanical heart valve is a clinical condition distinct from atrial fibrillation,” he explained. “In patients with a mechanical heart valve, coagulation activation and thrombin generation seem to be partially induced by the exposure of blood to the artificial surfaces of the valve leaflets and sewing ring (“contact thrombosis”), whereas in atrial fibrillation, under low blood flow conditions, thrombin generation is believed to be triggered by blood stasis and endothelial dysfunction.” A likely explanation for why warfarin is more effective in the setting of mechanical valves is that “warfarin also inhibits synthesis of factor IX of the contact pathway while dabigatran exclusively inhibits thrombin,” he added. If this hypothesis is correct, “the consequence could also be that factor Xa inhibitors such as rivaroxaban or apixaban won’t work for this indication and that patients with a mechanical heart valve will have to take warfarin or other vitamin K antagonists for the next 5 to 10 years,“ he said.

There are potentially many other explanations why dabigatran did not work in patients with mechanical heart valves (MHV) and these are related to pharmacokinetics as well as pharmacology. In this case, large peak-trough plasma level ratio may have played a role in addition to hyper-activated factor XII as well as platelet derived mediators (following contact activation) such as polyphosphates that have been shown to completely reverse the anticoagulant effects of direct thrombin and direct factor Xa inhibitors as well as heparin but only partially reduce the anticoagulation effect of the VKA, warfarin. This reduction was shown to be overcome by having more warfarin in the circulation which may explain why MHV patients need to be kept at a higher INR of 2.5-3.5.

We must thank Boehringer-Ingelheim and the investigators of RE-ALIGN study for being very courageous in releasing the full data set from the RE-ALIGN study. We hope other companies and experts also take a firm stance both in public and in professional arenas on the use of NOACs in MHV patients. Otherwise, in the absence of well-controlled clinical trials, the only way the world is going to know whether NOACs are safe or not in MHV patients is when multiple case-reports of death and disability from off-label use of NOACs in heart valve patients turn up in major cardiology journals and other news outlets.

Pursuing a communication strategy that suggests until solid clinical data in MHV patients is available for NOACs they could be used in these patients (since animal models are not predictive) may also kill any new drug development in this space. Therefore, prosthetic heart valve patients may very well end up continuing to have only one OAC, warfarin, for the rest of their lives, drug that has been shown to be sub-optimal in this patient group. This is not right.

Disclosure: We are involved in the development of tecarfarin, a novel late stage oral anticoagulant for patients with prosthetic heart valves (PHV) which by default may have now become the only new oral anticoagulant that may be used in patients with PHV. We will soon be releasing data from our last Phase III study (EMBRACE-AC, where 14% of the patients in the study had mechanical heart valves which is also the approximate % of “real world” prevalence for this indication). In this study, tecarfarin was well tolerated in patients with MHV (i.e. no thromboembolic events or bleeds up to one year of treatment) and was better than warfarin in terms of efficacy. Additionally, subject to regulatory acceptance, tecarfarin could become the only anti-coagulant in the history of medicine to have pregnancy category B since unlike warfarin, heparin or even NOACs, tecarfarin is negative on reprotoxicology studies.